tbuckley/cabot-search huggingface dataset:
Abstract P1042: Endothelial Hif-2α Expression Prevents Against Myocardial Infarction Induced Heart Failure And Cardiac Microvascular Barrier Dysfunction
Authors: Karim Ullah, lizhuo Ai, Lifeng Liu, Qin Zhang, Kaichao Pan, Albert Sitikov, James K Liao, Rongxue Wu
Journal: Circulation Research (2022)

Background: HIF pathway is quickly activated during myocardial ischemia after myocardial infarction(MI), and cardiac microvascular leakage contributes to heart tissue damage. HIF2α isprofoundly expressed in cardiac endothelial cells (ECs) and the embryonic deletion of HIF2Aresults in increased vascular permeability and aberrant ECs behavior. However, the direct roleof endothelial cell-specific HIF2α (ecHIF2α) in ischemic heart disease is not known. Wehypothesized that ecHIF2α expression in response to myocardial infarction (MI) is protectiveagainst heart failure through the reduction of cardiac ECs apoptosis and inflammation. Methods and Results: To address our hypothesis, we generated EC-specific inducible-HIF2α knockout mice (ecHIF2α -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice. To assess the functional role of HIF2α inischemic heart injury, we ligated the proximal left anterior descending coronary artery to induceMI using the same age and gender-matched ecHIF2α -/- and control ( Hif2a flox/flox ) mice. Cardiacfunction was determined by echocardiography after two and four weeks of ligation. Analysis ofechocardiography revealed worsened heart function, and Masson’s Trichrome stain displayedincreased fibrosis in ecHIF2α -/- mice. In vitro , ECIS analysis of isolated cardiac microvascularendothelial cells showed decreased endothelial barrier function in ecHIF2α -/- cells. In addition,hypoxic stimulation reduces the tube formation capacity in ecHIF2α-/- cells and is sensitive tohypoxia-induced early-stage apoptosis. Deletion of HIF2α, as well as its binding partner ARNT,increased the expression of several inflammatory genes, including IL-6. Interestingly,overexpression of ARNT alone abolishes the HIF2α deletion-induced inflammatory geneexpression. IL-6 protein levels in HIF2α deleted human aortic endothelial cells (HAoEC) show asignificant reduction (n=3-5, p&lt;0.001) in ARNT overexpressed ECs. Conclusion: Collectively our data revealed an essential role of endothelial HIF2α/ARNT in maintaining cardiacfunctions by increasing endothelial barrier function and decreasing inflammation. Therefore,HIF2A/ARNT could provide a potential therapeutic target for the treatment of ischemic heartdisease.
Abstract P1034: Neurohormonal Pathways Drive Postnatal Thermogenesis And Loss Of Cardiac Regenerative Potential
Authors: Guo Huang
Journal: Circulation Research (2022)

Why do mammalian organs including the heart lose regenerative potential during the perinatal window remains enigmatic. Through phylogenetic analysis of vertebrate cardiomyocyte ploidy as a proxy for cardiac regenerative potential, we uncover that certain monotreme, edentate, cetacean, chiropteran species have unusually high percentages of diploid cardiomyocytes in the adult heart. Cardiomyocyte abundance across 41 vertebrate species conforms to Kleiber's law, the 3/4-power law scaling of metabolism with bodyweight, and decreases when the standard metabolic rate and body temperature increase during the ectotherm-to-endotherm transition. Recently, following the fractal feature of the cardiovascular system, we further strengthen the link between endothermy and heart physiology. Thermogenesis increases by more than 10-fold during the ectotherm-to-endotherm transition requiring similar increases in blood flow and cardiac function that may impede heart regenerative potential. Moreover, we report sympathetic nerve-adrenergic receptor and thyroid hormone signaling as two major pathways promoting both thermogenesis and cardiomyocyte cell cycle arrest. Combined inhibition of postnatal adrenergic and thyroid hormone signaling results in juvenile mice with strikingly low body temperatures (~25 ° C), significantly elevated abundances of diploid cardiomyocytes (~60%), dramatically increased cardiomyocyte proliferation, and enhanced cardiac regenerative abilities when analyzed at postnatal day 14. Intriguingly, both neurohormonal pathways seem to be inactive in adult zebrafish hearts. Altogether, our findings support critical roles of two major thermogenic pathways in suppressing heart regenerative capacity, and implicate that the limited regenerative capacity in various adult mammalian tissues may be a tradeoff for the acquisition of endothermy in ontogeny and phylogeny.
Abstract P2002: Mst1 Suppresses Pressure Overload-induced Cardiac Hypertrophy But Reduces Cardiac Function Through PERK Phosphorylation
Authors: Risa Mukai, Soichiro Usui, Peiyong Zhai, Yasuki Nakada, Junichi Sadoshima
Journal: Circulation Research (2022)

Cardiac hypertrophy in response to hemodynamic overload is initially an adaptive mechanism to maintain normal cardiac function by reducing left ventricular (LV) wall stress. Conversely, insufficient hypertrophy could lead to elevated wall stress, causing increased cell death and cardiac dysfunction. The Hippo pathway plays an important role in determining organ size. Mammalian sterile 20-like kinase 1 (Mst1) is the key serine-threonine kinase in the Hippo pathway, controlling cell death, proliferation, and differentiation. Mice with cardiac-specific overexpression of Mst1 (Tg-Mst1) fail to develop compensatory hypertrophy despite LV dysfunction and dilation at baseline. To elucidate the mechanism through which Mst1 inhibits cardiac hypertrophy, pressure overload (PO) was imposed on WT and Tg-Mst1 mice by transverse aortic constriction (TAC). TAC-induced increases in LV weight/body weight were significantly suppressed in Tg-Mst1 mice (5.8 vs WT 5.1, p&lt;0.05). LV ejection fraction (EF) after TAC was lower in Tg-Mst1 mice than in WT mice (40% vs WT 60%, p&lt;0.01), consistent with the notion that Mst1 promotes PO-induced systolic dysfunction in part by inhibiting compensatory hypertrophy. Mst1 interacted with and induced phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). We generated knock-in mice expressing phosphorylation-resistant PERK (PERK-KI) and performed TAC on WT and PERK-KI mice. LVEF was preserved in PERK-KI mice compared to in WT mice (67% vs WT 46%, p&lt;0.05) after 8 weeks of TAC. PO-induced increases in lung congestion were attenuated in PERK-KI mice compared to in WT mice (10 vs WT 11.5, p&lt;0.05). Despite the improvement in cardiac function, cardiac hypertrophy was not attenuated in PERK-KI mice. These results suggest that phosphorylation of PERK by Mst1 is detrimental for the heart during PO, in part due to suppression of compensatory hypertrophy.
Abstract P3126: Sphingomyelinase Participates Diet - Induced Increases In Aortic Stiffness And Cardiac Dysfunction
Authors: Javad Habibi, Vincent G DeMarco, Jack L Hulse, Adam Whaley-Connell, Michael A Hill, James R Sowers, Guanghong Jia
Journal: Circulation Research (2022)

Excessive accumulation of ceramides induces mitochondria dysfunction and promotes toxicity in multiple types of cells, including endothelial cells and cardiomyocytes. Neutral sphingomyelinase (nSMase) is thought to increase ceramide levels through sphingomyelin hydrolysis, and the resultant increase in ceramides plays a role in the pathogenesis of a number of disorders, such as atherosclerosis and heart failure. While inhibition of nSMase attenuates the progression of atherosclerosis and heart failure, little is known regarding its role in correcting impaired metabolic signaling, arterial dysfunction and metabolic cardiomyopathy. Accordingly, we hypothesized that nSMase inhibition with GW4869, attenuates Western diet (WD) - induced increases in aortic stiffness and cardiac dysfunction through effects on pathways which lead to oxidative stress and inflammation. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 hours for 12 weeks). WD consumption increased plasma nSMase activation and tissue nSMase2 expression in concert with aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. WD fed mice exhibited reduced EF (systolic dysfunction) and increased E/E’ and IVRT (diastolic dysfunction) determined by in vivo Doppler ultrasound. Moreover, these functional abnormalities were associated with attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. These functional and metabolic abnormalities were blunted by in vivo GW4869 treatment. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and cardiac dysfunction by correction of impaired metabolic signaling.
Abstract P3083: Beta 1.3 1.6 D Glucan Immunomodulatory Activity Of Indonesian Ganoderma Lucidum Mycelium Extract In Repairing Heart Tissue And Function On Myocardial Infarction Patients
Authors: Peter Sugita, djanggan sargowo
Journal: Circulation Research (2022)

Introduction: Immune response plays a significant role in heart repair and regeneration after myocardial infarction and/or ischemia-reperfusion injury (MI/RI). Prolonged inflammation response contributes to adverse cardiac remodeling and reduction in pump function. In stable angina pectoris and patients with high-risk for heart disease, Beta 1.3 1.6 D Glucan has demonstrated reduced inflammation parameters including IL-6, TNF-α and CRP. Hypothesis: Beta 1.3 1.6 D Glucan modulates inflammation responses related to myocardial infarction or MI/RI, therefore preventing adverse heart remodeling measured by Left Ventricle Mass Index (LVMI) and Left Ventricle Ejection Fraction (LVEF). Method: In May - August 2018 a randomized double-blind placebo-controlled trial was conducted comprising of 50 STEMI/NSTEMI patients at the Saiful Anwar General Hospital, Malang, Indonesia. Next to standard therapy, 25 patients received Beta 1.3 1.6 D Glucan, 540 mg/day for 90 days, while the other 25 patients received placebo. Results: During the study duration, 5 patients dropped out. The mean value of pre-test LVMI for all patients is 114.07 ± 59.61 g/m 2 . After 90 days, there was a significant difference (p=0.012) in LVMI between the Beta 1.3 1.6 D Glucan and placebo group. The Beta 1.3 1.6 D Glucan group had a LVMI reduction of 4.55 ± 14.46 g/m 2 compared to the placebo group with an increase of 11.48 ± 23.94 g/m 2 in LVMI. The mean value of pre-test LVEF for all patients is 57.2 ± 11.39%. Post-test results demonstrated a significant difference (p=0.042) between both groups, with an increase in LVEF of 2.3 ± 9.77% for Beta 1.3 1.6 D Glucan group and a decrease in LVEF of 2.08 ± 3.35% for placebo group. Conclusion: Beta 1.3 1.6 D Glucan as an adjuvant therapy may have a beneficial effect to repair the vascular, heart tissues and function in myocardial infarction patients.
Abstract P2029: The Role Of Runx1 In Cardiomyocyte Cell Cycle Activity And Its Impact On Cardiac Regeneration
Authors: Kaelin A Akins, Samantha Swift, Mary Kolell, Michael Flinn, Caitlin Omeara, Michaela Patterson
Journal: Circulation Research (2022)

Factors responsible for cardiomyocyte proliferation may serve as a potential therapeutic to stimulate endogenous myocardial regeneration following insult, such as ischemic injury. A previously published forward genetics approach assessing the frequency of a rare and presumed proliferation-competent subpopulation of cardiomyocytes, mononuclear diploid cardiomyocytes (MNDCMs), led us to the transcription factor RUNX1. It is established that RUNX1 induction in cardiomyocytes increases after injury. Here, we examine the effect of RUNX1 on cardiomyocyte cell cycle and establishment of the MNDCM population during postnatal development and cardiac regeneration using both cardiomyocyte-specific gain-and loss of function mouse models. We hypothesize that RUNX1 overexpression (OE) increases cardiomyocyte cell cycle activity with expansion of the MNDCM population, thereby extending the neonatal regenerative window and positively impacting adult cardiac remodeling post injury. During postnatal development, RUNX1 KO decreased postnatal cardiomyocyte cell cycle activity, while RUNX1 OE extended the period of cell cycle activation. This extension observed in RUNX1 OE mice is complete with cytokinesis resulting in an expansion of the MNDCM population and total cardiomyocyte endowment. To determine whether RUNX1 could similarly regulate cardiomyocyte cell cycle in a regenerative and non-regenerative model, we induce P6 and 8-week MIs to measure cell cycle activity and cardiac function post injury. RUNX1 OE neonatal mice with a P6 MI displayed no difference in cardiomyocyte cell cycle activity 7 post injury compared to control littermates. However, RUNX1 OE in adult mice with an 8-week MI showed increased cardiomyocyte cell cycle activity with completion of cytokinesis 2 weeks post injury and limited improvement in cardiac function 28 days post injury. RUNX1 influences cardiomyocyte cell cycle activation in the context of normal postnatal development and adult MI. Conversely, this phenomenon does not appear to translate to the neonatal injury context. We are examining this possible discrepancy with further experiments to fully understand .
Abstract P2034: Photobiomodulation Accelerates Wound Healing In Heart Tissue
Authors: Keva Li, Cristina Florio, Christopher Morrell, Robert E Monticone, Bruce Ziman, Edward G Lakatta
Journal: Circulation Research (2022)

Cardiovascular diseases and aging induce stress on the heart, resulting in heart wall thickness and stiffness associated with increased fibrosis. The sinoatrial node (SAN) is the heart’s natural pacemaker composed of a fibrous tissue matrix with a heterogenous cellular population. With aging, activated fibroblasts can create scar tissue, thus commonly resulting in sick sinus syndrome (SSS) and arrhythmias. SSS is produced by idiopathic degeneration of the SAN, requiring implantation of electronic pacemakers. Phototherapy or photobiomodulation (PBM) is a technique with many therapeutic properties that has been applied clinically to treat various forms of tissue pathology. Although there has been evidence that PBM has positive effects on the heart to improve cardiac function and prevent infarction, its age associated changes during wound healing are unknown. This study uses timelapse microscopy and red light (630 nm) or near-infrared (NIR, 810 nm) PBM on SAN support cells (SANspc) isolated from 2 months (2mo) and 2 years (2y) old mice during in vitro wound healing. With an average initial gap width of 540 μm, the kinetics and extent of wound closure are measured for each of the SANspc age and treatment groups. Nonirradiated SANspc served as controls. Aging slowed kinetics and increased the extent of wound healing by an average of 1.87 hours earlier than that of the 2mo-SANspc (p &lt; 0.05). Irradiation with red light induces a significantly faster scale of closure for the gap width to close between ½ and ¾ by 0.25 and 0.68 hours, in 2mo- and 2y-SANspc respectively, compared to their corresponding age control. With red irradiation, 2y-SANspc resulted in a significantly faster scale of closure of 0.52 hours compared to 2mo-SANspc. Irradiation with NIR resulted in the opposite effect in both age groups, in which the scale of closure for the wound slowed significantly (0.19 and 0.71 hours in the 2mo- and 2y-SANspc, respectively). In conclusion, these data suggests that SANspc migration and proliferation capacity is faster with aging and red irradiation increases wound closing effect in both age groups. Thus, the enhanced wound healing induced by PBM may be an attractive therapeutic approach to target cardiac fibrosis and promote cardiac remodeling in the aging heart.
Abstract P1071: Concurrent Stat1 And Stat3 Signaling Modulates Tlr4/nfkb-mediated Immunomodulatory And Antifibrotic Effects Of Cardiomyocyte-damaged Released S100a1 Protein In Cardiac Fibroblasts
Authors: Martin Busch, Michael Daszenies, Patrick Most
Journal: Circulation Research (2022)

Background: We previously showed that S100A1 released from damaged cardiomyocytes can accelerate post-myocardial infarction in vivo healing. The action of S100A1 as a damage-associated molecular pattern seemed to occur via an immunomodulatory (e.g., IL10 increase) and antifibrotic impact (e.g., COL1A1 and ACTA2 downregulation) in cardiac fibroblasts (CFs) via a TRL4/NKFB pathway. The signaling network in CFs conveying this effect has not been characterized yet. Methods and Results: We performed a 48h time-resolved transcriptome analysis on cultured adult rat CF stimulated with rec. human S100A1 protein (10 -6 M). Bioinformatic GSEA yielded an instant and almost exclusive significant upregulation of the chemokine activity GO-term with a delayed suppression of ECM genes. A transcription factor enrichment analysis for the differentially regulated transcripts indicated an immediate activation of NFKB/RELA with a concurrent temporary STAT1 but lasting STAT3 signaling. A secretome LC-MS/MS-based analysis confirmed the shift of S100A1-treated CFs to mostly chemokine secreting cells. With CCL2 as most secreted chemokine and COL1A1 and ACTA2 as established antifibrotic marker genes for released S100A1, we used a RT-PCR readout for these genes in response to siRNA-based knock-down (KD) of STAT1 and STAT3 in S100A1-treated CFs, while TLR4 KD was used to abrogate NFKB/RELA signaling due to known mechanisms (n=10 each group). S100A1 treatment upregulated CCL2 (16-fold*) and downregulated COL1A1 (3.1-fold*) and ACTA2 (2.9-fold*) mRNA expression vs control (*P&lt;0.01) that was blunted by TLR4 KD. STAT3 KD doubled the CCL2 mRNA increase (32.9-fold*), attenuated COL1A1 mRNA downregulation by S100A1 treatment to 2-fold* but left ACTA2 downregulation unaffected vs contr. (*P&lt;0.05). Conversely, STAT1 KD completely blocked the S100A1 mediated downregulation of ACTA2 but neither impacted S100A1-mediated changes in CCL2 nor COL1A1. Conclusion: Our study identifies concurrent STAT1 and STAT3 activation as a modulator of S100A1-mediated TLR4-NFKB signaling in CFs. As S100A1-activated CFs express e.g., IL-10, we speculate that IL-gp130 trans signaling may convey this effect guiding further studies on S100A1’s extracellular effects in the diseased heart.
Abstract P3100: Integrating Single-Cell Transcriptomics And Light-Sheet Imaging To Elucidate The Mechanisms Of Cardiac Outflow Development
Authors: Jing Wang, Zhaoqiang (Aaron) Wang, Ryan O'donnell, Ching-Ling Lien, Tzung K Hsiai
Journal: Circulation Research (2022)

Introduction: Transcription factors Snai1 are recognized to regulate endo/epithelial-to-mesenchymal transitionduring cardiac morphogenesis. However, the relative importance of myocardial contractile vs. intracardiac fluidshear force-mediated Snai1 during outflow track (OFT) development remains undefined. Methods and Results: Using single-cell RNA analysis, we identified a population of epicardial Snai1b + cells inthe zebrafish hearts at 5-days post-fertilization that carry both smooth muscle cells and fibroblast markers. sc-RNA data from Weinberger et al. (2020) was analyzed via the scater package in R. Snai1b + cells in the Tg(Snai1b:EGFP; Flk:mCherry) embryos were localized by confocal microscopy and the real-time valvular dynamics by our custom-built 4-D (space + time) light-sheet fluorescence microscope (LSFM) at 200 frames/second. Consistent with Weinberger et al. (2020), Snai1b was highly expressed in the “Epi2” epicardial cluster (Elnb + /Mylka + / Sema3fb + ) ( Figure 1A, E-G ). In addition, this cluster expressed alpha-smooth muscle actin (a-SMA orActa2), vimentin (Vim), and fibronectin 1a (Fn1a). We also observed the activation of BMP-Snai-Pitx2 pathway, where Nodal and Pitx2 were suppressed due to the expression of BMPs and Snai1/2. Next, confocal imaging localized the Snai1b+ cells at the bulbus arteriosus (BA) base, separating the ventricle from the passiveBA ( Figure 1B ). LSFM further captured the moving boundary of endocardium in BA for intra-tissue strain and stress simulation ( Figure 1C ). Conclusions: Snai1b may contribute to OFT development in a myocardial contractile force- rather than intra-cardiac shear stress-dependent manner. This finding paves the way to elucidatethe 4-D genomic interaction between Snai1b + cells and developmental transcriptomics.
Abstract P3001: Hnrnpa2b1 An Rna-binding Protein That Orchestrates Smooth Muscle Cell Phenotype In Pulmonary Arterial Hypertension.
Authors: Gregoire Ruffenach, Lejla Medzikovic, Laila Aryan, Min Li, Mansoureh Eghbali
Journal: Circulation Research (2022)

Background: RNA-binding proteins (RPBs) are master orchestrators of gene expression regulation. RBPs regulate hundreds of transcripts at once by recognizing specific motifs. Characterizing RBP targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, limiting our understanding of their function. In cancer, the RBP HNRNPA2B1 (A2B1) promotes the pro-proliferative / anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMC) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH. Methods: Through the integration of computational and experimental biology, we investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA-sequencing allowed us to investigate the transcriptome-wide function of A2B1, while RNA immunoprecipitation and A2B1 silencing experiments in vitro allowed us to decipher the intricate molecular mechanism at play. In addition, we performed a pre-clinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity. Results: In the present study, we found that A2B1 is up-regulated in human PAH-PASMC. We also show that A2B1 localization shifts in PAH-PASMC from cytoplasmic to nuclear mainly due to significantly higher expression of B1 isoform compared to A2 isoform of A2B1. Using bio-informatics, we identified three known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, we demonstrated the complementary non-redundant function of A2B1 motifs as all motifs are implicated in different aspect of the cell cycle. In addition, we showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC lead to a decrease of all tested mRNAs carrying an A2B1 motif, and an according decrease in proliferation and resistance to apoptosis. Finally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. Conclusion: Through the integration of computational and experimental biology, our study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.